Oral Presentation 45th Lorne Genome Conference 2024

Enrichment of interrupted ATXN2 repeat expansion in a Parkinson's Disease cohort - a role for interrupted motifs in disease pleiotropy (#5)

Haloom Rafehi 1 2 , Longfei Wang 1 2 , Michael Milton 3 , Liam G Fearnley 1 2 , Mark F Bennett 1 2 4 , Melanie Bahlo 1 2
  1. Population Health and Immunity, WEHI, Parkville, Victoria, Australia
  2. Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
  3. Research Computing, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia
  4. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia

Repeat expansions (REs) of short tandem repeats (STRs) cause over 50 neurological and muscular disorders such as ataxia, sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although there are no REs that exclusively cause Parkinson’s disease (PD), some evidence suggests that REs that cause other neurodegenerative/neurological disorders may also contribute to the development of PD. For example, there are conflicting reports on whether the CAG RE in ATXN2 that causes spinocerebellar ataxia 2 (SCA2) causes PD when the STR is interrupted by CAA motifs. In this study, we used ExpansionHunter5 and REViewer to screen whole genome sequencing  from 3,016 people with PD and 3,224 controls from the Accelerating Medicines Partnership for Parkinson’s Disease (AMP-PD) repository, comprised of multiple PD cohorts, for 36 different disease caused by REs. We identified expanded ATXN2 RE in five PD cases and no controls. Four of these expansions were interrupted by CAA motifs, while one was a pure CAG motif. Our results confirm previous reports that interrupted ATXN2 REs may cause PD rather than ataxia. These findings suggest pathological pleiotropy of neurodegenerative disease genes and implicate repeat expansions in PD pathogenicity.